COLORECTAL BLEEDING:a multidisciplinary approach

Torino, 31 marzo-1 aprile 2006

GENETIC EVALUATION

Schena M, Angelini F, Bertetto O.Department of Medical Oncology, COES,

Ospedale S. Giovanni Battista, Torino, Italy.

COLORECTAL CANCER DISTRIBUTION

68%

25%

6% 1%SPORADICFAMILIALHNPCCFAP

COLON CANCER LIFE-TIME RISK

• Average risk US population 6%

• Familial predisposition 12-18%

• Hereditary Syndromes

HNPCC 70-80%

FAP 100%

HNPCC

Autosomal dominant hereditary cancer predisposition syndrome

Early onset of CRC (average age 44)

Frequent proximal colon distribution

Fast adenoma carcinoma evolution

Extracolonic cancers: endometrium, ovary, stomach, small bowel,hepatobiliary tract,ureter or renal pelvis, pancreas, brain.

HNPCC

Five different genes of DNA mismacth repair system:

MLH1, MSH2, MSH6, PMS1, PMS2

Germline inactivating mutation

Microsatellite instability (MSI)Loss of specific protein (IHC)

HNPCC genes Dominant autosomic inheritance

MLH1 (3p22.3 – 57 kb, 19 exons)

MSH2 (2p21- 80 kb, 16 exons)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

AMSTERDAM CRITERIA II

Three family members with HNPCC-related cancer (colon, endometrium, small bowel, kidney-renal pelvis, ureters), two first degree relatives

At least two successive generations affected

One relative diagnosed at less than age 50

GENETIC COUNSELING(minimal access criteria)

No family history (or very small family):2 HNPCC-related cancers in the same patientYoung age of onset (< 50 years old)

Families with two first-degree relatives affected:One with young age of onset (< 50 years old)Colon adenoma at young age (< 40 years old)

Families with three first or two-degree relatives affected at any age.

Pre-Test evaluation

MSI - Microsatellite Instability test -

IHC - Immunohystochemistry for MLH1, MSH2, MSH6 products -

GENETIC TEST

• Amsterdam II criteria

• MSI and IHC pre-test evaluation

Affected member of the family Age > 18

Genetic Counseling Informed consent

FAP

Colon cancer predisposition syndrome -100-1000 adenomatous colonic polyps develop (classic form); 20-100 adenomatous polyps (attenuated form)

Mean age of 16 years (range 7-36 years)

By age 35 years, 95% of individuals have polyps; incidence of colon cancer is 100%

Extracolic manifestations are variably present (polyps of the gastric fundus and duodenum, osteomas, dental anomalies,retinic spots,soft tissue tumors and associated cancers)

FAP Genes Dominant autosomic (APC) and

recessive (MYH) inheritance

APC (5q22.2 – 100 kb, 15 exons)

MYH (1p34.1- 11 kb, 16 exons) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

ACCESS CRITERIA

• Classic or attenuated adenomatous polyposis• Familial hystory of polyposis • Extracolic manifestations

Any Affected Subject

Genetic Counseling Informed consent

SURVEILLANCE CRITERIA IN HNPCC

Colonoscopy

EXAMSAGE OF START

EXAMS FREQUENCY COMMENTS

COLON CA

ENDOMETRIAL CA OVARIAN CA

GASTRIC CA

URETERAL CA

21 years

every 2 years up to 40 years

afterward yearly

TVUSfrom 23-35 years

every 1-2 years

EGDscopyfrom 20-35 years

every 1-2 years

US + citology

from 20-35 years

every 1-2 years

FAP SURVEILLANCE CRITERIA

Colonoscopy

EXAMSAGE OF START

EXAMS FREQUENCY COMMENTS

COLON CA

GASTRIC CA DUODENAL CA

THYROID CA

from puberty

yearly genetic counseling

APC research total colectomy

Gastro-duodenoscop

y

from 20-25 years

every 1-3 years

Thyroid examfrom 10-12 years

every 12 month

CONCLUSION

• Genetic syndromes are rare but show high lifetime risk of CRC with early onset

• The role of gastroenterologist and surgeon that manage colorectal bleeding is crucial to disclose family with high genetic risk

• Members of these families should be addressed to genetic counseling.

www.rigenio.it

HNPCC genes Dominant autosomic inheritance

MSH6 (2p16.3 – 24 kb, 10 exons)

PMS1 (

PMS2 (7p22.1- 36 kb, 15 exons)

The syndrome is the result of deficiencies in

mismatch repair genes

INCIDENCE OF COLORECTAL CANCER

35-40.000 new pt/year in Italy

3.300 new pt/year in Piemonte

670 new pt/year in Torino